Mitochondria are organelles each composed of an outer membrane and an inner membrane having a cristae structure, and are distributed throughout cytoplasm in a tubular reticular structure. Mitochondria also have their own genes (mitochondrial DNA) besides nuclear genes.
Mitochondria have the functions of, for example, producing energy which is necessary for activity of cells, and catalyzing biosynthesis and degradation of crucial biological substances. Mitochondria are also involved in other biological activities such as production of active oxygen and production of apoptosis-inducing signal.
Mitochondria dynamically change their forms by migration, fusion and disintegration in response to environmental changes in the cell. In particular, under the pathological conditions, such as the case of liver disease, congenital muscular dystrophy, gastric cancer, myeloma, and dilated cardiomyopathy due to abnormality of mitochondrial DNA, mitochondria significantly change their forms and distributions, and express megamitochondria, annular or axle form, or morphological and structural variations having an annular or concentric cristae structure.
As a mammalian gene in relation to these mitochondria, a gene involved in disintegration of mitochondria is known (J. Cell Biol. 143: 351–358, 1998). On the other hand, as a gene involved in fusion of mitochondria, a gene product Fzo expressed at the time of formation of sperm of drosophila, which promotes mitochondrial fusion (Cell 90: 121–129, 1997), and a gene product Fzo1p which promotes fusion of mitochondria occurring at the time of meiotic division of fission yeast (J. Cell Biol. 143: 359–373, 1998) are known. However, mammalian genes involved in fusion of mitochondria have not been identified.
Examples of the diseases caused by mutation of mitochondrial DNA include mitochondrial myopathy, cardiomyopathy, type II diabetes, Alzheimer's disease, Parkinson's disease and the like. Such a mutant mitochondrial DNA exists within a cell in the state of heteroplasmy wherein mutant mitochondrial DNA and normal mitochondrial DNA coexist. When the existing ratio of mutant DNA exceeds a predetermined threshold, the cell function deteriorates to lead appearance of disease symptoms. Gene therapeutic methods against these diseases have not been established because, unlike nuclear DNA, mitochondrial DNA exists in mitochondria. As a method which enables gene therapy targeted towards mitochondrial DNA, transfers of foreign mitochondria by means of cybrid method or microinjection (J. Cell Biol. 67: 174–188, 1975, Cell 52: 811–819, 1988) have been reported heretofore. However, these methods entail the drawbacks that large amounts of cytoplasm components other than mitochondria are introduced, and that desired genes and substances cannot be introduced into mitochondria. Therefore, they are far from actual use at present.
As described above, mitochondria changes their forms in accordance with the pathological condition of particular disease, and a protein promoting aggregation and fusion of mitochondria is thought to be involved in such a morphological change. Therefore, it is expected that isolation of human proteins as described above and detailed analysis of their functions will open new avenues for clarifying causes of mitochondrial diseases in human and developing preventive and therapeutic methods thereof. Moreover, it is expected that antibodies against such proteins and probes derived from genes encoding such proteins will be useful materials for diagnosing conditions of mitochondria in a particular disease.
Furthermore, protein samples which promote aggregation or fusion of mitochondria are expected to provide new measures for specific transfer of foreign genes and drugs targeted on mitochondria.